PROJECT SUMMARY/ABSTRACT Background: Several lines of evidence suggest that insomnia contributes to emotionally distressing depressive mood symptoms through disruption of brain networks that regulate emotional functions. Of particular concern, insomnia is associated with an increased risk for suicide, even when accounting for the presence of other depressive symptoms. However, we do not yet know to what degree that the emotion regulation brain network is modified by the restoration of sleep, or whether the degree to which a sleep intervention engages these neural targets mediates reductions in depressive symptoms and suicidality. Objective: This proposal investigates the impact of a proven sleep intervention on engagement of the emotion regulation brain network as a putative mechanistic target. DESIGN/METHODS: In the R61 phase, a mechanistic trial will demonstrate feasibility and establish whether the emotion regulation brain network is modified (the target is engaged) when patients show improvements in insomnia symptoms following a proven psychosocial sleep intervention. Participants will be 70 adults experiencing elevated depressive symptoms and clinically meaningful insomnia. Depressive symptoms and insomnia will be assessed prior to, and weekly while receiving six Cognitive Behavioral Therapy for Insomnia (CBT-I) sessions across a period of eight weeks. CBT-I improves sleep patterns through a combination of sleep restriction, stimulus control, mindfulness training, cognitive therapy targeting dysfunctional beliefs about sleep, and sleep hygiene education. Emotion regulation network neural targets will be assayed prior to and following completion of CBT-I treatment. If the Go milestone criteria are met, the R33 phase (years 3-5) will include a 2-arm randomized controlled trial. We will enroll new participants (n=150) and randomize them in a 1:1 ratio to the CBT-I or to the credible control treatment for insomnia group. Participants will complete a refined measurement protocol based on the R61 phase study. Specific aims: R61 aims are to demonstrate (1) feasibility and (2) that CBT-I modifies emotion regulation network function according to pre-specified Go milestone criteria. R33 aims are to (1) confirm target engagement by testing the hypothesis that compared with an active control condition, CBT-I participants will show significant change in the emotion regulation network targets that met the Go Criteria of Study 1 in the direction of normalization, at the end of treatment, (2) examine the relationships of target engagement to treatment outcomes by study group, and (3) test whether emotion regulation network measures at baseline predict depressive symptom and suicidality reduction. IMPACT: Characterizing these associations may offer the potential to gain a deeper understanding of the neurobiological mechanisms underlying depression in the presence of insomnia. Our results will advance an evidence-based mechanistic approach to treating, and ultimately preventing, the emotionally distressing and potentially life-threatening impact of insomnia.